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Molecular and Cellular Biology

Jae Ho Lee, Yong Geun Jeon, Kyoung-Hwa Lee, Hye Won Lee, Jeu Park, Hagoon Jang, Minyong Kang, Hye Sun Lee, Hee Jin Cho, Do-Hyun Nam, Cheol Kwak, Jae Bum Kim
Elevated lipid metabolism promotes cancer cell proliferation. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers, characterized by ectopic lipid accumulation. However, the relationship between aberrant lipid metabolism and tumorigenesis in ccRCC is not thoroughly understood. Here, we demonstrate that ring finger protein 20 (RNF20) acts as a tumor suppressor in ccRCC. RNF20 overexpression repressed lipogenesis and cell proliferation by inhibiting sterol regulatory element-binding protein 1c (SREBP1c), and SREBP1 suppression by either knockdown or the pharmacological inhibitor betulin attenuated proliferation and cell cycle progression in ccRCC cells...
August 21, 2017: Molecular and Cellular Biology
Ryan M Bradley, Emily B Mardian, Darin Bloemberg, Juan J Aristizabal Henao, Andrew S Mitchell, Phillip M Marvyn, Katherine A Moes, Ken D Stark, Joe Quadrilatero, Robin E Duncan
We previously characterized LPAATδ/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here we report that Lpaatδ (-/-) mice display impaired spatial learning and memory compared to wildtype littermates in the Morris Water Maze, and investigated potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged...
August 14, 2017: Molecular and Cellular Biology
Lei Yu, Takashi Moriguchi, Hiroshi Kaneko, Makiko Hayashi, Atsushi Hasegawa, Masahiro Nezu, Hideyuki Saya, Masayuki Yamamoto, Ritsuko Shimizu
Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia-reperfusion injury (IRI)...
August 14, 2017: Molecular and Cellular Biology
Michael C Reubens, Sophie Rozenzhak, Paul Russell
DNA replication involves the inherent risk of genome instability, as replisomes invariably encounter DNA lesions or other structures that stall or collapse replication forks during S-phase. In the fission yeast Schizosaccharomyces pombe, the multi-BRCT domain protein Brc1, which is related to budding yeast Rtt107 and mammalian PTIP, plays an important role in maintaining genome integrity and cell viability when cells experience replication stress. The C-terminal pair of BRCT domains in Brc1 were previously shown to bind phospho-histone H2A (γH2A) formed by Rad3/ATR checkpoint kinase at DNA lesions; however, the putative scaffold interactions involving the N-terminal BRCT domains 1-4 of Brc1 have remained obscure...
August 7, 2017: Molecular and Cellular Biology
Yiming Li, Meng Chen, Juan Liu, Lianyun Li, Xiao Yang, Jiao Zhao, Min Wu, Mei Ye
MicroRNAs (miRNAs) exhibit aberrant expression in the initiation and progression of a variety of human cancers including colorectal cancer (CRC). However the exact mechanisms are not well defined. MiRNA expression profiles were characterized by microarrays in CRC samples and miR-18b was increased significantly in tumor tissues. The expression of miR-18b was confirmed in CRC cell lines SW480 and HCT116 and 44 clinical specimens by qRT-PCR. Multiple linear regression analysis showed a strong correlation of miR-18b expression with lymph node and distant metastasis...
August 7, 2017: Molecular and Cellular Biology
Jianli Gong, Misun Park, Susan F Steinberg
Protein kinase Cδ (PKCδ) is an allosterically-activated enzyme that acts much like other PKC isoforms to transduce growth factor-dependent signaling responses. However, PKCδ is unique in that activation loop (Thr(507)) phosphorylation is not required for catalytic activity. Since PKCδ can be proteolytically-cleaved by caspase-3 during apoptosis, the prevailing assumption has been that the kinase domain fragment (δKD) freed from autoinhibitory constraints imposed by the regulatory domain is catalytically competent - and that Thr(507) phosphorylation is not required for δKD activity...
August 7, 2017: Molecular and Cellular Biology
Hugo Sepulveda, Alejandro Villagra, Martin Montecino
Here we assess histone modification, chromatin remodeling and DNA methylation processes that coordinately control the expression of the bone master transcription factor Sp7 (Osterix) during mesenchymal lineage commitment in mammalian cells. We find that Sp7 gene silencing is mediated by DNMT1/3a-, HDAC1/2/4-, Setdb1/Suv39h1- and Ezh1/2-containing complexes. In contrast, Sp7 gene activation involves changes in histone modifications, accompanied by decreased nucleosome enrichment and DNA demethylation mediated by SWI/SNF- and Tet1/Tet2-containing complexes, respectively...
August 7, 2017: Molecular and Cellular Biology
Chuanhe Yu, Haiyun Gan, Zhiguo Zhang
Three DNA polymerases (Pol α, Pol δ, and Pol ϵ) are responsible for eukaryotic genome duplication. When DNA replication stress is encountered, DNA synthesis stalls until the stress is ameliorated. However, it is not known whether there is a difference in the association of each polymerase with active and stalled replication forks. Here, we show that each DNA polymerase has distinct patterns of association with active and stalled replication forks. Pol α is enriched at extending Okazaki fragments of active and stalled forks...
August 7, 2017: Molecular and Cellular Biology
Emily G Kaye, Amina Kurbidaeva, Daniel Wolle, Tsutomu Aoki, Paul Schedl, Erica Larschan
CES (chromatin entry sites) are 100-1,500 bp elements that recruit MSL (Male Specific Lethal) complexes to the X-chromosome to upregulate expression of X-linked genes in male flies. CES contain one or more ∼20 bp GA rich sequences called MREs (MSL recognition elements) that are critical for dosage compensation. Recent studies indicate that CES also correspond to boundaries of X-chromosomal TADs (topologically associated domains). Here we show that a ∼1,000 kDa complex called the LBC, which is required for the functioning of the Bithorax complex boundary Fab-7, interacts specifically with a special class of CES that contain multiple MREs...
August 7, 2017: Molecular and Cellular Biology
Joshua M Dewe, Benjamin L Fuller, Jenna M Lentini, Stefanie M Kellner, Dragony Fu
Mutations in the tRNA methyltransferase 1 (TRMT1) gene have been identified as the cause of certain forms of autosomal recessive intellectual disability (ID). However, the molecular pathology underlying ID-associated TRMT1 mutations is unknown since the biological role of the encoded TRMT1 protein remains to be determined. Here, we have elucidated the molecular targets and function of TRMT1 to uncover the cellular effects of ID-causing TRMT1 mutations. Using human cells that have been rendered deficient in TRMT1, we show that TRMT1 is responsible for catalyzing the dimethylguanosine (m2,2G) base modification in both nuclear and mitochondrial-encoded tRNAs...
August 7, 2017: Molecular and Cellular Biology
Peyman P Aryanpur, Chelsea A Regan, John M Collins, Telsa M Mittelmeier, David M Renner, Ashley M Vergara, Nicolette P Brown, Timothy A Bolger
DEAD-box proteins (DBPs) are required in gene expression to facilitate changes to ribonucleoprotein complexes, but the cellular mechanisms and regulation of DBPs are not fully defined. Gle1 is a multifunctional regulator of DBPs with roles in mRNA export and translation. In translation, Gle1 modulates Ded1, a DBP required for initiation. However, DED1 overexpression causes defects, suggesting that Ded1 can promote or repress translation in different contexts. Here we show that GLE1 expression suppresses the repressive effects of DED1 in vivo, and Gle1 counteracts Ded1 in translation assays in vitro Furthermore, Ded1 and Gle1 both affect assembly of pre-initiation complexes...
August 7, 2017: Molecular and Cellular Biology
Mohammad B Hossain, Rehnuma Shifat, Jingyi Li, Xuemei Luo, Kenneth R Hess, Yisel Rivera-Molina, Francisco P Martinez, Hong Jiang, Frederick F Lang, Mien-Chie Hung, Juan Fueyo, Candelaria Gomez-Manzano
DNA repair pathways are aberrant in cancer, enabling tumor cells to survive standard therapies-chemotherapy and radiotherapy. Our group previously reported that, upon irradiation, the membrane-bound tyrosine kinase receptor TIE2 translocates into the nucleus and phosphorylates histone H4 at Tyr51, recruiting ABL1 to the DNA repair complexes that participate in the non-homologous end-joining pathway. However, no specific molecular mechanisms of TIE2 endocytosis have been reported. Here, we show that irradiation or ligand-induced TIE2 trafficking is dependent on caveolin-1, the main component of caveolae...
July 31, 2017: Molecular and Cellular Biology
Siddharth Shukla, Roy Parker
Loss-of-function mutations in 3' -5' exoribonucleases have been implicated in hereditary human diseases. For example, PARN mutations cause a severe form of dyskeratosis congenita (DC), wherein PARN deficiency leads to human telomerase RNA instability. Since the DC phenotype in PARN patients is even more severe than loss-of-function alleles in telomerase components, we hypothesized that PARN would also be required for the stability of other RNAs. Here, we show that PARN depletion reduces the levels of abundant human Y RNAs, which might contribute to the severe phenotype of DC observed in patients...
July 31, 2017: Molecular and Cellular Biology
Vanessa Weis, Sebastian Königsberger, Susanne Amler, Jürgen Wienands, Friedemann Kiefer
The non-receptor tyrosine kinase Syk, a central regulator of immune cell differentiation and activation, is a promising drug target for treatment of leukemia, allergic and inflammatory diseases. The clinical failure of Syk inhibitors underscores the importance to understand the regulation of Syk function and activity.A series of previous studies emphasized the importance of three C-terminal tyrosines in Syk for kinase activity regulation, as docking sites for downstream effector molecules and for Ca(2+) mobilization...
July 31, 2017: Molecular and Cellular Biology
Jaewon Min, Woodring E Wright, Jerry W Shay
Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers. By analyzing telomerase positive cells and their hTERC knockout derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems. ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner. Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in S...
July 31, 2017: Molecular and Cellular Biology
Marianne Land, Charles S Rubin
Ca(2+) and diacylglycerol (DAG) activated protein kinase C (cPKC) promotes learning and behavioral plasticity. However, knowledge of in vivo regulation and exact functions of cPKCs that affect behavior is limited. We show that PKC-2, a C. elegans cPKC, is essential for a complex behavior, thermotaxis. C. elegans memorizes a nutrient-associated cultivation temperature (Tc) and migrates along Tc within a 17-25°C gradient. pkc-2 gene disruption abrogated thermotaxis; a PKC-2 transgene, driven by endogenous pkc-2 promoters, restored thermotaxis behavior in pkc-2(-/-) animals...
July 17, 2017: Molecular and Cellular Biology
Stephanie Valtierra, Zhiqiang Du, Liming Li
Saccharomyces cerevisiae contains several prion elements, which are epigenetically transmitted as self-perpetuating protein conformations. One such prion is [SWI(+) ], whose protein determinant is Swi1, a subunit of the SWI/SNF chromatin-remodeling complex. We previously reported that [SWI(+) ] formation results in a partial loss-of-function phenotype of poor growth in non-glucose media and abolishment of multicellularity. We also showed that the first 38 amino acids of Swi1 propagated [SWI(+)]. We show here that a region as small as the first 32 amino acids of Swi1 (Swi11-32) can decorate [SWI(+)] aggregation and stably maintain and transmit [SWI(+)] independently of full-length Swi1...
July 17, 2017: Molecular and Cellular Biology
Emma M Quinlan, Justin J King, Chris T Amemiya, Ellen Hsu, Mani Larijani
Activation induced cytidine deaminase (AID) is a genome-mutating enzyme that initiates class switch recombination and somatic hypermutation of antibodies in jawed vertebrates. We previously described the biochemical properties of human AID and found that it is an unusual enzyme in that it exhibits binding affinities for its substrate DNA and catalytic rates several orders of magnitude higher and lower, respectively, than a typical enzyme. Recently, we solved the functional structure of AID and demonstrated that these properties are due to non-specific DNA binding on its surface, along with a catalytic pocket that predominantly assumes a closed conformation...
July 17, 2017: Molecular and Cellular Biology
Yuan Zhang, Yun Zhang, Lan Xiao, Ting-Xi Yu, Jun-Zhe Li, Jaladanki N Rao, Douglas J Turner, Myriam Gorospe, Jian-Ying Wang
Insulin-like growth factor type-2 (IGF2) receptor (IGF2R) recognizes mannose 6-phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBP) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA-195 (miR-195) and the RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells...
July 17, 2017: Molecular and Cellular Biology
Yixin Dong, Kyo-Ichi Isono, Kazuyuki Ohbo, Takaho A Endo, Osamu Ohara, Mamiko Maekawa, Yoshiro Toyama, Chizuru Ito, Kiyotaka Toshimori, Kristian Helin, Narumi Ogonuki, Kimiko Inoue, Atsuo Ogura, Kazutsune Yamagata, Issay Kitabayashi, Haruhiko Koseki
Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian Nucleosome acetyltransferase of H4 (NuA4) complexes, are co-expressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development...
July 10, 2017: Molecular and Cellular Biology
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